Durability of Complete Responses in Patients With Metastatic Cancer Treated With High-Dose Interleukin-2. Identification of the Antigens Mediating Response

Rosenberg, Sanders D.; Yang, J. C.; White, D. E.; Steinberg, S. M.

doi:10.1097/00005392-199908000-00129

Cited by 66 publications

(75 citation statements)

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“…These cells also play a key role in the protection against cancer (Multhoff et al 1995a;Rosenberg et al 1998;Whiteside et al 1998;Farag et al 2002). For some time, the low-affinity Fcγ receptor CD16, which mediates antibody-dependent cellular cytotoxicity (Lanier et al 1988), and the homophilic adhesion molecule CD56 were the only known human NK cell receptors.…”

Section: Discussionmentioning

confidence: 99%

Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells

Stangl

Groß

Pockley

et al. 2008

Cell Stress and Chaperones

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This study compared the effects of the human 70-kDa stress protein (Hsp70) peptide, TKDNNLL GRFELSG (TKD), proinflammatory cytokines, or a combination of both on the repertoire of receptors expressed by human natural killer (NK) cells and their capacity to kill human CX colon carcinoma cells, K562 erythroleukemic cells, and leukemic blasts from two patients with acute myelogenous leukemia. Low-dose interleukin (IL) 2/IL-15 and TKD increase the expression density of activatory (NKG2D, NKp30, NKp44, NKp46, CD94/NKG2C) and inhibitory (CD94/NKG2A) receptors on NK cells. Concomitantly, IL-2/TKD treatment enhances the cytotoxicity of NK cells (as reflected by their secretion of granzyme B) against Hsp70 membrane-positive and human leukocyte antigen (HLA)-E membrane-negative (Hsp70 + /HLA-E − ) CX + and K562 cells. However, it had no effect on the responsiveness to Hsp70 Hsp70-blocking and HLA-E transfection experiments confirmed membrane-bound Hsp70 as being a recognition/ activatory ligand for NK cells, as cytotoxicity was reduced by the presence of the anti-Hsp70 monoclonal antibody cmHsp70.2 and by inhibiting Hsp70 synthesis using short interference ribonucleic acid. HLA-E was confirmed as an inhibitory ligand, as the extent of NK cell-mediated lysis of K562 cell populations that had been transfected with HLA-E R or HLA-E G alleles was dependent on the proportion of HLA-E-expressing cells. These findings indicate that Hsp70 (as an activatory molecule) and HLA-E (as an inhibitory ligand) expression influence the susceptibility of leukemic cells to the cytolytic activities of cytokine/TKDactivated NK cells.

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Section: Discussionmentioning

confidence: 99%

Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells

Stangl

Groß

Pockley

et al. 2008

Cell Stress and Chaperones

View full text Add to dashboard Cite

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“…Furthermore, local administration of cytokines is not always possible owing to the tumor location. Targeting inflammatory cytokines such as IL-2 (Rosenberg et al, 1998), granulocyte macrophage colony-stimulating factor (Robinson et al, 1998), IL-12 (Soiffer et al, 1993) and more, to tumors via tumorspecific antibody or antibody fragments, has proven to induce effective antitumor response. The purpose of cytokine antibody conjugates modality is to widen the therapeutic window and to induce antitumor immune response by achieving high concentrations of proinflammatory cytokines in the vicinity of the tumor cells.…”

Section: Ab-cytokines/chemokines Conjugatesmentioning

confidence: 99%

Novel antibodies as anticancer agents

2007

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In recent years antibodies, whether generated by traditional hybridoma technology or by recombinant DNA strategies, have evolved from Paul Ehrlich's 'magic bullets' to a modern age 'guided missile'. In the recent years of immunologic research, we are witnessing development in the fields of antigen screening and protein engineering in order to create specific anticancer remedies. The developments in the field of recombinant DNA, protein engineering and cancer biology have let us gain insight into many cancer-related mechanisms. Moreover, novel techniques have facilitated tools allowing unique distinction between malignantly transformed cells, and regular ones. This understanding has paved the way for the rational design of a new age of pharmaceuticals: monoclonal antibodies and their fragments. Antibodies can select antigens on both a specific and a high-affinity account, and further implementation of these qualities is used to target cancer cells by specifically identifying exogenous antigens of cancer cell populations. The structure of the antibody provides plasticity resonating from its functional sites. This review will screen some of the many novel antibodies and antibody-based approaches that are being currently developed for clinical applications as the new generation of anticancer agents.

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“…Interleukin-2 (IL-2) has resulted in durable responses and cure in 5 -7% of the patients (Rosenberg et al, 1998;Atkins et al, 2000). Meta-analyses on patients receiving IL-2-based immunotherapy have identified independent prognostic factors of survival such as serum lactate dehydrogenase (LDH), number of metastatic sites and performance status (Eton et al, 1998;Keilholz et al, 1998Keilholz et al, , 2002Manola et al, 2000).…”

mentioning

confidence: 99%

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

et al. 2005

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We aimed to create a prognostic model in metastatic melanoma based on independent prognostic factors in 321 patients receiving interleukin-2 (IL-2)-based immunotherapy with a median follow-up time for patients currently alive of 52 months (range 15 -189 months). The patients were treated as part of several phase II protocols and the majority received treatment with intermediate dose subcutaneous IL-2 and interferon-a. Neutrophil and monocyte counts, lactate dehydrogenase (LDH), number of metastatic sites, location of metastases and performance status were all statistically significant prognostic factors in univariate analyses. Subsequently, a multivariate Cox's regression analysis identified elevated LDH (Po0.001, hazard ratio 2.8), elevated neutrophil counts (P ¼ 0.02, hazard ratio 1.4) and a performance status of 2 (P ¼ 0.008, hazard ratio 1.6) as independent prognostic factors for poor survival. An elevated monocyte count could replace an elevated neutrophil count. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the three independent prognostic factors. Low-, intermediate-and high-risk patients achieved a median survival of 12.6 months (95% confidence interval (CI), 11.4 -13.8), 6.0 months (95% CI, 4.8 -7.2) and 3.4 months (95% CI, 1.2 -5.6), respectively. The low-risk group encompassed the majority of long-term survivors, whereas the patients in the high-risk group with a very poor prognosis should probably not be offered IL-2-based immunotherapy.

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Durability of Complete Responses in Patients With Metastatic Cancer Treated With High-Dose Interleukin-2. Identification of the Antigens Mediating Response

Cited by 66 publications

References 0 publications

Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells

Influence of Hsp70 and HLA-E on the killing of leukemic blasts by cytokine/Hsp70 peptide-activated human natural killer (NK) cells

Novel antibodies as anticancer agents

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

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